Following a myocardial infarction (MI), impaired microvascular blood flow (BF) results in loss of cardiomyocyte function and, if untreated, can lead to widespread left ventricular (LV) contractile failure. Protecting the integrity and function of the microcirculation following MI remains a major target of cardiac regenerative medicine in order to prevent the progressive dysfunctional pathological changes that lead to eventual myocardial necrosis. The extent of unviable myocardium within an infarct region after coronary vessel occlusion depends on several factors, including time to reperfusion, collateral vessel development potential, and possible ischemic preconditioning. See Ragosta M, Powers E R, Samady H, Gimple L W, Sarembock I J, and Beller G A. Relationship between extent of residual myocardial viability and coronary flow reserve in patients with recent myocardial infarction. Am Heart J 141: 456-462, 2001. The most traditional clinical treatment for acute MI is coronary revascularization of the infarct-related artery, specifically percutaneous coronary intervention (PCI), thrombolysis, or bypass surgery. However, as many as 48% of PCI patients do not regain distal microvascular perfusion even though the suspect artery is angiographically open. See Feldman L J, Himbert D, Juliard J M, Karrillon G J, Benamer H, Aubry P, Boudvillain O, Seknadji P, Faraggi M, and Steg G. Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size. J Am Coll Cardiol 35: 1162-1169, 2000. As such, there is a clinical need for treatments that are developed specifically with regard to coronary microcirculatory development, maintenance, and repair.
Recent approaches to treat ischemia have focused on injection of suspensions of regenerative therapies including direct injection of growth factors, cytokines, and/or progenitor cells. Cellular therapy has been limited by lack of retention of injected cells, as only ˜1.3-2.6% of transplanted cells are retained in the infarcted myocardium after intracoronary injection. See Hofmann M, Wollert K C, Meyer G P, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp W H, and Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111: 2198-2202, 2005. Additionally, a recent study by Hamdi H et al, Epicardial adipose stem cell sheets results in greater post-infarction survival than intramyocardial injections, Cardiovasc Res 91: 483-491, 2011, showed that an adipose cell sheet implant resulted in greater post-infarct survival and greater cell engraftment than intramyocardial injections of the same cells. Therefore, more approaches have begun to focus on a combination of cell therapy and scaffolds to address the inadequate retention, survival, and integration of injected cells into the host tissue. Cellular and acellular cardiac patches (Badylak S, Obermiller J, Geddes L, and Matheny R. Extracellular matrix for myocardial repair. Heart Surg Forum 6: E20-26, 2003; Kellar R S, Shepherd B R, Larson D F, Naughton G K, and Williams S K. Cardiac patch constructed from human fibroblasts attenuates reduction in cardiac function after acute infarct. Tissue Eng 11: 1678-1687, 2005; Leor J, Aboulafia-Etzion S, Dar A, Shapiro L, Barbash I M, Battler A, Granot Y, and Cohen S. Bioengineered cardiac grafts: A new approach to repair the infarcted myocardium? Circulation 102: 11156-61, 2000) as well as injectable in situ gelling materials (Lu W N, Lu S H, Wang H B, Li D X, Duan C M, Liu Z Q, Hao T, He W J, Xu B, Fu Q, Song Y C, Xie X H, and Wang C Y. Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A 15: 1437-1447, 2009) have all been explored for use as cardiac repair therapies focused on rebuilding myocardial tissue and/or microcirculatory repair. For example, muscle patches paired with genetically engineered mesenchymal stem cells (MSC) (Huang W, Zhang D, Millard R W, Wang T, Zhao T, Fan G C, Ashraf A, Xu M, Ashraf M, and Wang Y. Gene manipulated peritoneal cell patch repairs infarcted myocardium. J Mol Cell Cardiol 48: 702-712), progenitor cells combined with MSCs (Derval N, Barandon L, Dufourcq P, Leroux L, Lamaziere J M, Daret D, Couffinhal T, and Duplaa C. Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model. Eur J Cardiothorac Surg 34: 248-254, 2008), and bone marrow cells in a collagen matrix (Barandon L, Couffinhal T, Dufourcq P, Alzieu P, Daret D, Deville C, and Duplaa C. Repair of myocardial infarction by epicardial deposition of bone-marrow-cell-coated muscle patch in a murine model. Ann Thorac Surg 78: 1409-1417, 2004) have all been somewhat effective at improving overall heart function after MI when compared to untreated hearts. Although increasing viable myocardial tissue remains critical to post-MI hearts, another major component of treatment should focus on coronary microcirculatory repair in order to supply adequate blood flow to transplanted cardiomyocytes.